The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC50 = 12 nM) that binds with high affinity (K-i = 0.3 nM) and functional selectivity (> 50-fold over the mu-, kappa-, and beta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R, 4R)-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/ kg i. p.), SCH 221510 (1-30 mg/ kg p.o.) produced anxiolytic- like effects in the elevated plus- maze ( rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation- induced vocalization ( guinea pig) assays. In the Vogel conflict, the anxiolytic- like effect of SCH 221510 (10 mg/ kg) was attenuated by J-113397 (3-10 mg/ kg p. o.), but not naltrexone (3-30 mg/ kg i.p.). Additionally, the anxiolytic- like effects of SCH 221510 did not change appreciably following 14- day b.i. d. dosing in rats (10 mg/ kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/ kg) produced anxiolytic- like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side- effect liability.